SUMMARY/ABSTRACT Human African Trypanosomiasis (HAT) is caused by the protozoan Trypanosoma brucei. New drugs need to be developed to treat the disease because the currently approved therapies are not orally bioavailable and some are toxic. We have evaluated a class of carbazole-based small molecules called ?Curaxins? as possible hits for anti-trypanosome lead discovery. Eleven of the 27 Curaxins tested had growth inhibitory concentrations (GI50) lower than 100 nM. Curaxin-137 (CBL0137) cured 100% of mice infected with T. brucei, after oral dosing with no observed toxicity, making it a new lead for anti-trypanosome drugs. Curaxin-137 was detected in the brain of mice at a concentration that was 4-fold higher than found in blood, and 1000-times higher than GI50. These data suggest that the drug is highly likely to cure stage 2 HAT, when trypanosomes have crossed the blood-brain barrier. We have identified two hits CBL0174 and CBL0187 that could serve as backups for CBL0137, and enable us to embark on preclinical studies for development of CBL0137. Our immediate goals are to (i) evaluate CBL0137's efficacy in stage 2 HAT; (ii) profile the metabolic, pharmacological, pharmacokinetic, blood-brain barrier permeability, and physiochemical features in vitro, as well as safety, and toxicity of CBL0174 and CBL0187 so as to determine whether they could be used in mouse models of HAT, and (iii) synthesize new analogs CBL0137 that are optimized for brain penetrance, while preserving selectivity, metabolic, physicochemical, and pharmacokinetic/ADME properties. Our preliminary structure-activity relationship data have revealed structural alterations of CBL0137 that may be implemented to improve efficacy as well as other properties of Curaxins. Newly-synthesized compounds that meet our screening thresholds and also cure HAT in the mouse model will serve backup leads as we advance those that cure stage 2 HAT as preclinical candidates for anti-trypanosome drug development.